The Past, Present, and Future in the Diagnosis of a Neglected Sexually Transmitted Infection: Trichomoniasis.

More than one million curable sexually transmitted infections occur every day. is one of the main infections responsible for these epidemiological data; however, the diagnosis of this protozoan is still mainly based on microscopic and culture identification. The commercialization of immunological tests and the development of molecular techniques have improved the sensitivity of classical methods.

Promising hit compounds against resistant trichomoniasis: Synthesis and antiparasitic activity of 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles.

A series of 11 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles (2-12) has been prepared starting from 1-benzyl-5-nitroindazol-3-ol 13, and evaluated against sensitive and resistant isolates of the sexually transmitted protozoan Trichomonas vaginalis. Compounds 2, 3, 6, 9, 10 and 11 showed trichomonacidal profiles with IC < 20 µM against the metronidazole-sensitive isolate. Moreover, all these compounds submitted to cytotoxicity assays against mammalian cells exhibited low non-specific cytotoxic effects, except compounds 3 and 9 which displayed moderate cytotoxicity (CC = 74.

Antichagasic, Leishmanicidal, and Trichomonacidal Activity of 2-Benzyl-5-nitroindazole-Derived Amines.

Three different series of new 5-nitroindazole derivatives-1-(ω-aminoalkyl)-2-benzylindazolin-3-ones (series A; ten compounds), 3-(ω-aminoalkoxy)-2-benzylindazoles (series B; four compounds) and 3-alkylamino-2-benzylindazoles (series C; five compounds)-have been synthesized and evaluated against the protozoan parasites Trypanosoma cruzi, Leishmania amazonensis, and Trichomonas vaginalis: etiological agents of Chagas disease, cutaneous leishmaniasis, and trichomoniasis, respectively. Many indazoles of series A, B, and C were efficient against T. cruzi.

Drug repositioning for novel antitrichomonas from known antiprotozoan drugs using hierarchical screening.

Aim: Metronidazole is the most widely used drug in trichomoniasis therapy. However, the emergence of metronidazole-resistant Trichomonas vaginalis isolates calls for the search for new drugs to counter the pathogenicity of these parasites.

Results: Classification models for predicting the antitrichomonas activity of molecules were built.

Antichagasic and trichomonacidal activity of 1-substituted 2-benzyl-5-nitroindazolin-3-ones and 3-alkoxy-2-benzyl-5-nitro-2H-indazoles.

Two series of new 5-nitroindazole derivatives, 1-substituted 2-benzylindazolin-3-ones (6-29, series A) and 3-alkoxy-2-benzyl-2H-indazoles (30-37, series B), containing differently functionalized chains at position 1 and 3, respectively, have been synthesized starting from 2-benzyl-5-nitroindazolin-3-one 5, and evaluated against the protozoan parasites Trypanosoma cruzi and Trichomonas vaginalis, etiological agents of Chagas disease and trichomonosis, respectively. Many indazolinones of series A were efficient against different morphological forms of T. cruzi CL Brener strain (compounds 6, 7, 9, 10 and 19-21: IC50 = 1.

In vitro trichomonacidal activity and preliminary in silico chemometric studies of 5-nitroindazolin-3-one and 3-alkoxy-5-nitroindazole derivatives.

A selection of 1,2-disubstituted 5-nitroindazolin-3-ones (1-19) and 3-alkoxy-5-nitroindazoles substituted at positions 1 (20-24) or 2 (25-39) from our in-house compound library were screened in vitro against the most common curable sexually transmitted pathogen, Trichomonas vaginalis. A total of 41% of the studied molecules (16/39) achieved a significant activity of more than 85% growth inhibition at the highest concentration assayed (100 µg mL(-1)). Among these compounds, 3-alkoxy-5-nitroindazole derivatives 23, 24, 25 and 27 inhibited parasite growth by more than 50% at 10 µg mL(-1).

Sequestration of host-CD59 as potential immune evasion strategy of Trichomonas vaginalis.

Trichomonas vaginalis is known to evade complement-mediated lysis. Because the genome of T. vaginalis does not possess DNA sequence with homology to human protectin (CD59), a complement lysis restricting factor, we tested the hypothesis that host CD59 acquisition by T.

Synthesis and in vitro and in vivo biological evaluation of substituted nitroquinoxalin-2-ones and 2,3-diones as novel trichomonacidal agents.

Two series of ten novel 7-nitroquinoxalin-2-ones and ten 6-nitroquinoxaline-2,3-diones with diverse substituents at positions 1 and 4 were synthesized and evaluated against the sexually transmitted parasite Trichomonas vaginalis. Furthermore, diverse molecular and drug-likeness properties were analyzed to predict the oral bioavailability following the Lipinski's "rule of five". 7-Nitroquinoxalin-2-one derivatives displayed moderate to high in vitro activity while the efficiency of most nitroquinoxaline-2,3-diones was rather low; both kinds of compounds did not show cytotoxic effects in mammalian cells.

A sequential procedure for rapid and accurate identification of putative trichomonacidal agents.

In the current report, a sequential step-wise methodology based on in silico, in vitro and in vivo experimental procedures for the prompt detection of potential trichomonacidal drugs is proposed. A combinatorial of 12 QSAR (Quantitative Structure-Activity Relationship) models based on Linear Discrimination Analysis (LDA) are suggested for the rational identification of new trichomonacidal drugs from virtual screening of in house chemical libraries and drug databases. Subsequently, compounds selected as potential anti-trichomonas are screened in vitro against Trichomonas vaginalis.

Determination of internal transcribed spacer regions (ITS) in Trichomonas vaginalis isolates and differentiation among Trichomonas species.

The nucleotide sequence of the 5.8S rRNA gene and the flanked internal transcribed spacer (ITS) regions of six Trichomonas vaginalis isolates with different metronidazole sensitivity and geographic origin were genotyped. A multiple sequence alignment was performed with different sequences of other isolates available at the GenBank/EMBL/DDBJ databases, which revealed 5 different sequence patterns.

Synthesis and antimalarial activity of new heterocyclic hybrids based on chloroquine and thiazolidinone scaffolds.

A series of new 21 chloroquine heterocyclic hybrids containing either benzylamino fragment or N-(aminoalkyl)thiazolidin-4-one moiety were synthesized and screened for their antimalarial activity against chloroquine (CQ)-sensitive 3D7 and multidrug-resistance Dd2 strains of Plasmodium falciparum. Although no compounds more active than CQ against 3D7 was found; against Dd2 strain, six compounds, four of them with benzylamino fragment, showed an excellent activity, up to 3-fold more active than CQ. Non specific cytotoxicity on J774 macrophages was observed in some compounds whereas only two of them showed liver toxicity on HepG2 cells.

New 1-aryl-3-substituted propanol derivatives as antimalarial agents.

This paper describes the synthesis and in vitro antimalarial activity against a P. falciparum 3D7 strain of some new 1-aryl-3-substituted propanol derivatives. Twelve of the tested compounds showed an IC(50) lower than 1 microM.

Synthesis and evaluation of 1,1'-hydrocarbylenebis(indazol-3-ols) as potential antimalarial drugs.

Bis(indazol-3-ol) derivatives (5, 30-38) were prepared by alkylation of 3-alkoxyindazoles with alpha,omega-dibromides, followed by removal of the O-protecting groups. These compounds were subsequently evaluated as inhibitors of biocrystallization of ferriprotoporphyrin IX (heme) to hemozoin, a Plasmodium detoxification specific process. Most bis(5-nitroindazol-3-ols) were good inhibitors, however, a denitro analogue (38), the intermediate bis(3-alkoxyindazoles) (15-29) as well as bis(indazolin-3-ones) (39-42) were not active, showing the importance of the NO(2) and OH groups in the inhibition process.

Immunomodulation of the response to excretory/secretory antigens of Fasciola hepatica by Anapsos in Balb/C mice and rat alveolar macrophages.

It is known that excretory/secretory antigens of Fasciola hepatica (ESFh) trigger a Th2-like immune response. Anapsos (A) is an aqueous hydrosoluble extract obtained from the rhizomes of the fern Polypodium leucotomos that has shown immunomodulator effects in some parasitic infections and immunological disorders. In this work we assess the effect of Anapsos and ESFh and Quillaja saponaria extract (Qs) on BALB/c mice and rat alveolar macrophages.

Synthesis and evaluation of some lipidic aminoalcohols and diamines as immunomodulators.

Lymphoproliferation inhibition and cytotoxicity of a number of lipidic aminoacids, aminoalcohols and diamines were evaluated as a preliminary screening to select potential immunomodulators. The four most potent/less toxic compounds were submitted to delayed hypersensibility (DTH) assays to define the best to be evaluated further Graft-vs-Host, NO production and other immunoevaluation (CD4(+), CD45, CD8, CD11b, I-Ek, and NK cells) assays, to establish their immunomodulation potential for being further considered as auxiliary agents for vaccination against some parasitic infections. Compounds 5d, 6d, 6f, 7a, and 9a, fairly inhibited the lymphoproliferation (71.

Trichinella: differing effects of antigens from encapsulated and non-encapsulated species on in vitro nitric oxide production.

Trichinellosis is a cosmopolitan zoonotic disease affecting a wide variety of animals, including man. Non-encapsulated and encapsulated species diverge with respect to their developmental strategies. Little is known at the molecular level about parasite-derived mediators responsible for host muscle cell transformation occurring during trichinellosis.

Predicting antitrichomonal activity: a computational screening using atom-based bilinear indices and experimental proofs.

Existing Trichomonas vaginalis therapies are out of reach for most trichomoniasis people in developing countries and, where available, they are limited by their toxicity (mainly in pregnant women) and their cost. New antitrichomonal agents are needed to combat emerging metronidazole-resistant trichomoniasis and reduce the side effects associated with currently available drugs. Toward this end, atom-based bilinear indices, a new TOMOCOMD-CARDD molecular descriptor, and linear discriminant analysis (LDA) were used to discover novel, potent, and non-toxic lead trichomonacidal chemicals.

Non-stochastic quadratic fingerprints and LDA-based QSAR models in hit and lead generation through virtual screening: theoretical and experimental assessment of a promising method for the discovery of new antimalarial compounds.

In order to explore the ability of non-stochastic quadratic indices to encode chemical information in antimalarials, four quantitative models for the discrimination of compounds having this property were generated and statistically compared. Accuracies of 90.2% and 83.

A computer-based approach to the rational discovery of new trichomonacidal drugs by atom-type linear indices.

Computational approaches are developed to design or rationally select, from structural databases, new lead trichomonacidal compounds. First, a data set of 111 compounds was split (design) into training and predicting series using hierarchical and partitional cluster analyses. Later, two discriminant functions were derived with the use of non-stochastic and stochastic atom-type linear indices.

A linear discrimination analysis based virtual screening of trichomonacidal lead-like compounds: outcomes of in silico studies supported by experimental results.

A computational (virtual) screening test to identify potential trichomonacidals has been developed. Molecular structures of trichomonacidal and non-trichomonacidal drugs were represented using stochastic and non-stochastic atom-based quadratic indices and a linear discrimination analysis (LDA) was trained to classify molecules regarding their antiprotozoan activity. Validation tests revealed that our LDA-QSAR models recognize at least 88.

Synthesis and antiparasitic properties of new 4-N-benzylamino-4-hetarylbut-1-enes.

New derivatives of 4-N-benzylamino-4-hetarylbut-1-ene containing a pyridyl nucleus were synthesized from benzylamines and pyridine aldehydes. N-oxide derivatives were obtained from these homoallylamines. Study of the antiparasitic properties of obtained pyridine derivatives as well as of four related benzazepines previously described, was carried out using cytotoxicity assays against Trichomonas vaginalis and epimastigote form of Trypanosoma cruzi protozoa.

4-Aryl(benzyl)amino-4-heteroarylbut-1-enes as building blocks in heterocyclic synthesis. 4. Synthesis of 4, 6-dimethyl-5-nitro(amino)-2-pyridylquinolines and their antiparasitic activities.

New nitro- and aminoquinoline derivatives containing a pyridyl nucleus were synthesized from 6, 8-disubstituted 4-methyl-2-pyridylquinolines, which were prepared from N-pyridylmethylidenanilines. The anti-chagasic and trichomonacidal in vitro activity, as well as the cytotoxic properties towards macrophages of some of these compounds were evaluated. Although some of the compounds showed only moderate activity it was possible to establish some structure-activity relationships.

Biological variability in clinical isolates of Trichomonas vaginalis.

Eighteen clinical isolates of Trichomonas vaginalis were obtained from women who attended health centers of the Government of Madrid. A total of 1,848 vaginal specimens recovered during the gynaecological examination were seeded in culture tubes containing liquid Diamond medium. Pathogenicity to mice was determined after intraperitoneal inoculation of mice by quantification of mortality and gross damage to abdominal organs.